Evidence of progressive abnormal brain development in schizophrenia
has emerged from the first longitudinal brain imaging study ever conducted
in adolescents for any illness. MRI (magnetic resonance imaging) scans
revealed ventricles (fluid-filled cavities in the middle of the brain)
enlarging between ages 14 and 16 in teens with a rare, severe, childhood
onset form of the disorder, report Judith Rapoport, M.D., and colleagues
of the National Institute of Mental Health, in the October issue of
the Archives of General Psychiatry.

Also in this issue, NIMH's Theodore Zahn, Ph.D., Rapoport and colleagues
report that the same adolescents, all of whom had experienced psychosis
prior to age 12, showed autonomic nervous system abnormalities characteristic
of adult schizophrenia.

"These and other studies add to mounting evidence that the childhood
and adult forms are the same illness," said Rapoport, Chief of the NIMH
Child Psychiatry Branch. "Understanding what's happening in these young
people during this period of highly volatile brain development may provide
clues about risk factors and neurodevelopmental abnormalities involved
in the much more common adult onset schizophrenia. Adults with the disorder
may well have experienced the same kind of abnormal brain changes during
their teens."

Affecting about 1 percent of adults, but only about .005 percent of
children, schizophrenia is the most chronic and disabling mental illness.
It typically begins as a psychotic episode in young adulthood, with
devastating hallucinations, delusions, social withdrawal, blunted emotionality
and loss of social and personal care skills. A new generation of antipsychotic
medications, such as clozapine, has helped many patients manage their
symptoms with fewer side effects.

In the MRI study, the researchers compared scans of 16 ill teenagers
participating in a clozapine trial with those of 24 age-matched controls.
At the initial scan, the youths with schizophrenia tended to show enlarged
ventricles, reduced total cerebral volume, and other structural anomalies.
After two years, a series of re-scans revealed "highly significant"
increases in the size of ventricles among those with schizophrenia.
The controls showed no significant changes.

Although adult schizophrenia patients tend to have enlarged ventricles,
evidence for progressive brain changes in adults has been more equivocal.
Absent signs of an ongoing illness process, one prevailing theory has
held that schizophrenia likely stems from damage caused by a prenatal
event - such as a viral infection in the womb, or some other environmental
insult to the developing brain -- that interacts with normal brain development
and life stresses, in genetically vulnerable individuals, to produce
the disorder in young adulthood. While not one of its original tenets,
the findings of progressive brain changes in adolescence are not inconsistent
with this "neurodevelopmental" hypothesis, say the researchers.

Unlike in adults, schizophrenia usually emerges gradually in children,
and is often preceded by developmental disturbances, such as lags in
motor and speech development. Adolescents in the study who had histories
of such autistic-like behavior tended to show greater ventricular enlargement.
Childhood onset schizophrenia also tends to be harder to treat and to
have a worse prognosis than the adult onset form. However, in a series
of studies over the past few years, Rapoport's group has shown that
affected children share with adults a similar pattern of brain structure
abnormalities and physiological features. For example, in the study
led by Zahn, the researchers report that the ill children had skin conductance
and heart rate anomalies similar to those seen in affected adults.

In interpreting the imaging findings, Rapoport and colleagues suggest
that the scans captured changes in the brain during a critical period
in development when it is "uniquely sensitive" to effects of the illness.
It's unlikely that the ventricles would continue enlarging at such a
high rate, "as that would produce improbably large ventricular volume
later in life," they note. Also, the "possibility that clozapine treatment
accelerates adolescent brain change can not be ruled out," they add.

The 16 affected adolescents in the study were the first to be re-scanned
from a total of 30 patients in the clozapine trial. Their MRI scans
were compared with scans from an ongoing NIMH study designed to provide
data on normal brain development during childhood and adolescence.

"The study of childhood onset cases presents a unique approach to schizophrenia,"
said Rapoport. "If we can understand what turns on the illness in these
rare cases, it may provide clues about how to turn it off for others."